Project Summary/Abstract The objective of this proposal is to provide Dr. Wolfgram a pathway to independence as a clinical investigator and expert in the field of cognitive and functional outcomes in adults on dialysis. The overall goal of Dr. Wolfgram is to improve the health and well-being of patients with end stage renal disease (ESRD) treated with hemodialysis (HD) by dedicating her career to evaluation, prevention and management of the cognitive and functional impairment that is highly prevalent in the HD population. In this proposal Dr. Wolfgram will focus on evaluation of a HD process-specific risk factor for cognitive decline in a HD cohort. The current literature and Dr. Wolfgram?s prior work suggest that, in addition to traditional patient risk factors for cognitive impairment, the HD process may further contribute to cognitive decline. Conventional HD causes circulatory stress that can lead to perfusion abnormalities and ischemic injury in end-organs. Brain injury, specifically, may occur due to changes in cerebral perfusion during HD. Patients on HD may have impaired cerebral auto-regulation due to vascular disease from common comorbid conditions such as diabetes, hypertension, and older age and from ESRD-specific risk factors such as vascular calcification from impaired calcium and phosphate regulation. Cerebral hypo-perfusion may occur during HD sessions due to systemic hemodynamic fluctuation in the setting of impaired cerebral autoregulation. This may lead to cerebral ischemic injury and subsequent cognitive decline. In this proposal Dr. Wolfgram will conduct a prospective cohort study evaluating intradialytic change in cerebral perfusion as a risk factor for decline in cognitive status. Dr. Wolfgram will use cerebral oximetry, measured by near-infrared spectroscopy, as an index for cerebral perfusion during HD sessions. She will evaluate three cognitive focused outcomes 1) cerebral white matter integrity measured with brain MRI, 2) cognitive performance measured with neuropsychological tests in the NIH Toolbox cognition battery, and 3) patient reported cognitive function measured with the Patient Reported Outcomes Measurement Information Systems. Results of this study will determine if changes in cerebral oximetry during HD are predictive of decline in cognitive outcomes overtime, and potentially identify a target for future therapeutic intervention aimed at reducing cognitive decline. In order to complete this study and achieve her goal of developing expertise in clinical outcomes research in the HD population Dr. Wolfgram will follow a career development training plan focused on research methodology, cerebral imaging, neuropsychology, and patient reported outcome measures. Her training will be guided by her mentor and advisors at the Medical College of Wisconsin, the Berman Center for Clinical Outcomes Research and Marquette University. Completion of this research proposal along with the formal training activities will allow Dr. Wolfgram to lead research work aimed at reducing the cognitive and functional impairment that is highly prevalent in our HD population.